Comprehensive molecular profiling of lung adenocarcinoma

Eric A. Collisson, Joshua D. Campbell, Angela N. Brooks, Alice H. Berger, William Lee, Juliann Chmielecki, David G. Beer, Leslie Cope, Chad J. Creighton, Ludmila Danilova, Li Ding, Gad Getz, Peter S. Hammerman, D. Neil Hayes, Bryan Hernandez, James G. Herman, John V. Heymach, Igor Jurisica, Raju Kucherlapati, David Kwiatkowski, Marc Ladanyi, Gordon Robertson, Nikolaus Schultz, Ronglai Shen, Rileen Sinha, Carrie Sougnez, Ming-Sound Tsao, William D. Travis, John N. Weinstein, Dennis A. Wigle, Matthew D. Wilkerson, Andy Chu, Andrew D. Cherniack, Angela Hadjipanayis, Mara Rosenberg, Daniel J. Weisenberger, Peter W. Laird, Amie Radenbaugh, Singer Ma, Joshua M. Stuart, Lauren Averett Byers, Stephen B. Baylin, Ramaswamy Govindan, Matthew Meyerson, Mara Rosenberg, Stacey B. Gabriel, Kristian Cibulskis, Carrie Sougnez, Jaegil Kim, Chip Stewart, Lee Lichtenstein, Eric S. Lander, Michael S. Lawrence, Gad Getz, Cyriac Kandoth, Robert Fulton, Lucinda L. Fulton, Michael D. McLellan, Richard K. Wilson, Kai Ye, Catrina C. Fronick, Christopher A. Maher, Christopher A. Miller, Michael C. Wendl, Christopher Cabanski, Li Ding, Elaine Mardis, Ramaswamy Govindan, Chad J. Creighton, David Wheeler, Miruna Balasundaram, Yaron S. N. Butterfield, Rebecca Carlsen, Andy Chu, Eric Chuah, Noreen Dhalla, Ranabir Guin, Carrie Hirst, Darlene Lee, Haiyan I. Li, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Richard Varhol, A. Gordon Robertson, Natasja Wye, Nina Thiessen, Robert A. Holt, Steven J. M. Jones, Marco A. Marra, Joshua D. Campbell, Angela N. Brooks, Juliann Chmielecki, Marcin Imielinski, Robert C. Onofrio, Eran Hodis, Travis Zack, Carrie Sougnez, Elena Helman, Chandra Sekhar Pedamallu, Jill Mesirov, Andrew D. Cherniack, Gordon Saksena, Steven E. Schumacher, Scott L. Carter, Bryan Hernandez, Levi Garraway, Rameen Beroukhim, Stacey B. Gabriel, Gad Getz, Matthew Meyerson, Angela Hadjipanayis, Semin Lee, Harshad S. Mahadeshwar, Angeliki Pantazi, Alexei Protopopov, Xiaojia Ren, Sahil Seth, Xingzhi Song, Jiabin Tang, Lixing Yang, Jianhua Zhang, Peng-Chieh Chen, Michael Parfenov, Andrew Wei Xu, Netty Santoso, Lynda Chin, Peter J. Park, Raju Kucherlapati, Katherine A. Hoadley, J. Todd Auman, Shaowu Meng, Yan Shi, Elizabeth Buda, Scot Waring, Umadevi Veluvolu, Donghui Tan, Piotr A. Mieczkowski, Corbin D. Jones, Janae V. Simons, Matthew G. Soloway, Tom Bodenheimer, Stuart R. Jefferys, Jeffrey Roach, Alan P. Hoyle, Junyuan Wu, Saianand Balu, Darshan Singh, Jan F. Prins, J.S. Marron, Joel S. Parker, D. Neil Hayes, Charles M. Perou, Jinze Liu, Leslie Cope, Ludmila Danilova, Daniel J. Weisenberger, Dennis T. Maglinte, Philip H. Lai, Moiz S. Bootwalla, David J. Van Den Berg, Timothy Triche Jr, Stephen B. Baylin, Peter W. Laird, Mara Rosenberg, Lynda Chin, Jianhua Zhang, Juok Cho, Daniel DiCara, David Heiman, Pei Lin, William Mallard, Douglas Voet, Hailei Zhang, Lihua Zou, Michael S. Noble, Michael S. Lawrence, Gordon Saksena, Nils Gehlenborg, Helga Thorvaldsdottir, Jill Mesirov, Marc-Danie Nazaire, Jim Robinson, Gad Getz, William Lee, B. Arman Aksoy, Giovanni Ciriello, Barry S. Taylor, Gideon Dresdner, Jianjiong Gao, Benjamin Gross, Venkatraman E. Seshan, Marc Ladanyi, Boris Reva, Rileen Sinha, S. Onur Sumer, Nils Weinhold, Nikolaus Schultz, Ronglai Shen, Chris Sander, Sam Ng, Singer Ma, Jingchun Zhu, Amie Radenbaugh, Joshua M. Stuart, Christopher C. Benz, Christina Yau, David Haussler, Paul T. Spellman, Matthew D. Wilkerson, Joel S. Parker, Katherine A. Hoadley, Patrick K. Kimes, D. Neil Hayes, Charles M. Perou, Bradley M. Broom, Jing Wang, Yiling Lu, Patrick Kwok Shing Ng, Lixia Diao, Lauren Averett Byers, Wenbin Liu, John V. Heymach, Christopher I. Amos, John N. Weinstein, Rehan Akbani, Gordon B. Mills, Erin Curley, Joseph Paulauskis, Kevin Lau, Scott Morris, Troy Shelton, David Mallery, Johanna Gardner, Robert Penny, Charles Saller, Katherine Tarvin, William G. Richards, Robert Cerfolio, Ayesha Bryant, Daniel P. Raymond, Nathan A. Pennell, Carol Farver, Christine Czerwinski, Lori Huelsenbeck-Dill, Mary Iacocca, Nicholas Petrelli, Brenda Rabeno, Jennifer Brown, Thomas Bauer, Oleg Dolzhanskiy, Olga Potapova, Daniil Rotin, Olga Voronina, Elena Nemirovich-Danchenko, Konstantin V. Fedosenko, Anthony Gal, Madhusmita Behera, Suresh S. Ramalingam, Gabriel Sica, Douglas Flieder, Jeff Boyd, JoEllen Weaver, Bernard Kohl, Dang Huy Quoc Thinh, George Sandusky, Hartmut Juhl, Edwina Duhig, Peter Illei, Edward Gabrielson, James Shin, Beverly Lee, Kristen Rodgers, Dante Trusty, Malcolm V. Brock, Christina Williamson, Eric Burks, Kimberly Rieger-Christ, Antonia Holway, Travis Sullivan, Dennis A. Wigle, Michael K. Asiedu, Farhad Kosari, William D. Travis, Natasha Rekhtman, Maureen Zakowski, Valerie W. Rusch, Paul Zippile, James Suh, Harvey Pass, Chandra Goparaju, Yvonne Owusu-Sarpong, John M. S. Bartlett, Sugy Kodeeswaran, Jeremy Parfitt, Harmanjatinder Sekhon, Monique Albert, John Eckman, Jerome B. Myers, Richard Cheney, Carl Morrison, Carmelo Gaudioso, Jeffrey A. Borgia, Philip Bonomi, Mark Pool, Michael J. Liptay, Fedor Moiseenko, Irina Zaytseva, Hendrik Dienemann, Michael Meister, Philipp A. Schnabel, Thomas R. Muley, Martin Peifer, Carmen Gomez-Fernandez, Lynn Herbert, Sophie Egea, Mei Huang, Leigh B. Thorne, Lori Boice, Ashley Hill Salazar, William K. Funkhouser, W. Kimryn Rathmell, Rajiv Dhir, Samuel A. Yousem, Sanja Dacic, Frank Schneider, Jill M. Siegfried, Richard Hajek, Mark A. Watson, Sandra McDonald, Bryan Meyers, Belinda Clarke, Ian A. Yang, Kwun M. Fong, Lindy Hunter, Morgan Windsor, Rayleen V. Bowman, Solange Peters, Igor Letovanec, Khurram Z. Khan, Mark A. Jensen, Eric E. Snyder, Deepak Srinivasan, Ari B. Kahn, Julien Baboud, David A. Pot, Kenna R. Mills Shaw, Margi Sheth, Tanja Davidsen, John A. Demchok, Liming Yang, Zhining Wang, Roy Tarnuzzer, Jean Claude Zenklusen, Bradley A. Ozenberger, Heidi J. Sofia, William D. Travis, Richard Cheney, Belinda Clarke, Sanja Dacic, Edwina Duhig, William K. Funkhouser, Peter Illei, Carol Farver, Natasha Rekhtman, Gabriel Sica, James Suh, Ming-Sound Tsao

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.